Multiple endocrine neoplasia type 4: a new member of the MEN family

Abstract

Objective: Multiple endocrine neoplasia type 4 (MEN4) is caused by a CDKN1B germline mutation first described in 2006. Its estimated prevalence is less than 1/million. The aim of this study was to define the disease characteristics. Methods: Systematic review according to the PRISMA 2020 criteria. MEDLINE® and Web of ScienceTM search from January 2006 to August 2022. Results: Forty-eight symptomatic patients fulfilled the pre-defined eligibility criteria. Twenty-eight different CDKN1B variants, mostly missense (21/48, 44%) and frameshift mutations (17/48, 35%), were reported. The majority of patients were women (36/48, 75%). Men became symptomatic at a median age of 32.5 years (range 10-68, mean 33.7 ± 23), whereas the same event was recorded for women at a median age of 49.5 years (range 5-76, mean 44.8 ± 19.9) (p = 0.25). The most frequently affected endocrine organ was the parathyroid gland (36/48, 75%; uniglandular disease 31/36, 86%), followed by the pituitary gland (21/48, 44%; hormone-secreting 16/21, 76%), the endocrine pancreas (7/48, 15%) and the thyroid gland (4/48, 8%). Tumours of the adrenal glands and thymus were found in three and two patients, respectively. The presenting first endocrine pathology concerned the parathyroid (27/48, 56%) and the pituitary gland (11/48, 23%). There were one (27/48, 56%), two (13/48, 27%), three (3/48, 6%), or four (5/48, 10%) syn- or metachronously affected endocrine organs in a single patient, respectively. Conclusion: MEN4 is an extremely rare disease, which most frequently affects women around 50 years of age. Primary hyperparathyroidism as a uniglandular disease is the leading pathology.

Management of surgical diseases of Primary Hyperparathyroidism: indications of the United Italian Society of Endocrine Surgery (SIUEC)

“…Primary HPT is common to both MEN1 [ 45 ], or Wermer’s syndrome (with associated tumors of the pituitary gland, endocrine pancreas and digestive tract) and MEN2A [ 46 ], or Sipple’s syndrome (with associated pheochromocytoma and medullary thyroid cancer) and the recently describe MEN4 [ 47 ].…”

An Update on the Genetic Drivers of Corticotroph Tumorigenesis

“…Germline LOF variants Five cases [125] (1.2% out of 245 paediatric cases in one cohort [33]) MEN4, isolated paediatric CD SDHA Germline LOF variant One case (1.2% out of 245 paediatric cases in one cohort [29]) Isolated paediatric CD, possibly: 3PAs PRKAR1A Germline LOF variants Three cases [156][157][158] (0.4% out of 245 paediatric cases in one cohort [33]) CNC RET Germline GOF variants Two cases [142] 3PAs, MEN2B DICER1…”

Hereditary Syndromes Associated with Pancreatic and Lung Neuroendocrine Tumors

“…Multiple endocrine neoplasia 4 (MEN4) syndrome is caused by germline mutations in the cyclin-dependent kinase (CDK) inhibitor 1b gene ( CDKN1B ) which encodes for the p27 Kip1 , commonly referred to as 27 or KIP1 [ 5 , 122 ]. CDKN1B is a tumor suppressor gene that regulates cell cycle progression, and its mutations affect the cellular localization of p27, stability, or binding [ 5 ].…”